The present invention relates to novel neurotensin mimetics useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are analgesics and are also useful as antipsychotic agents for treating psychoses such as schizophrenia.
Neurotensin (NT), an endogenous tridecapeptide found in the central nervous system (CNS), has been postulated to be a neurotransmitter or neuromodulator. A wide range of pharmacological effects have been attributed to NT. Two important aspects of NT actions on the CNS are its possible involvement in the etiology of schizophrenia (Nemeroff C, et al, Neuropsychopharm 1991;4:27 and its analgesic properties (Clineschmidt BJ, et al, European Journal of Pharmacology 1979;54:129-159). Thus, it has been suggested that NT may have neuroleptic-like activity within the CNS. Garver DL, et al, Am J Psychiatry 1991;148:484-8 reported data that showed diminished availability of NT in some psychotic patients with increases in neurotensin early in neuroleptic treatment. These results suggest that a NT agonist would be useful as an antipsychotic agent.
Furthermore, Clineschmidt BJ, et al, European Journal of Pharmacology 1979;54:129-139 reported an analgesic effect when NT was administered intracisternally to rodents. These results suggest that a NT agonist would be useful as an analgesic agent.
The C-terminal hexapeptide fragment of NT (NT(8-13)) has been shown to retain much of the activity found in the native peptide. Indeed, NT or NT(8-13) have been shown to possess activity in preclinical antinociceptive tests and in animal behavioral tests predictive of antipsychotic efficacy (Ervin G, et al, Nature 1981;29:73-76). NT(8-13) is metabolically unstable and this would limit its use as a therapeutic agent. Studies of the catabolism of NT(8-13) in various brain regions have revealed several key amide bonds which are most susceptible to proteolytic degradation (Davis TP, et al, Journal of Neurochemistry 1992;58:608-617). Compounds with sufficient metabolic stability may when administered peripherally remain intact long enough to diffuse or be transported across the blood brain barrier and interact with central NT receptors.
European Published Patent Application EP-0333071 disclosed a series of hexapeptide NT analogs of Formula I EQU A-B-C-D-E-F-R.sup.1 (I) EQU ( Seq ID No: 1)
wherein A stands for a group ##STR1## (G stands for a basic amino acid of L- or D-form, and R.sup.2 and R.sup.3, which may be the same or different, each stands for a hydrogen atom, a lower alkyl group, or an acyl group), a group ##STR2## (in which G stands for a basic amino acid of L- or D-form, J stands for an amino acid of L- or D-form, and R.sup.4 stands for a hydrogen atom or a lower alkyl group), an .omega.-aminoalkanoyl group ##STR3## (in which R.sup.5 and R.sup.6, which may be the same or different, each stands for a-hydrogen atom or a lower alkyl group, and m is an integer of from 1 to 10), or an .omega.-guanidinoalkanoyl group ##STR4## (in which n is an integer of from 1 to 10), or a group having the formula ##STR5## in which R.sup.11 is hydrogen or a lower alkyl, p is zero or an integer of from 1 to 10, B is a basic amino acid of L-form or an .alpha.-N-alkyl derivative thereof, C stands for L-Pro or a derivative thereof, D stands for a natural or nonnatural aromatic amino acid of L-form, E stands for an amino acid of L-form or an .alpha.-N-alkyl derivative or .alpha.-C-alkyl derivative thereof, F stands for an amino acid of L- or D-form or an .alpha.-N-alkyl derivative or .alpha.-C-alkyl derivative thereof, and R.sup.1 stands for a group ##STR6## (in which R.sup.7 and R.sup.8, which may be the same or different, each stands for a hydrogen atom or a lower alkyl group) or a group --O--R.sup.9 (in which R.sup.9 stands for a hydrogen atom, an alkyl group, an alkenyl group or a group --(CH.sub.2).sub.p --O--R.sup.10 in which p is an integer of from 1 to 5 and R.sup.10 stands for an alkyl group, an alkenyl group, or an acyl group).
This series of peptides was purported to be useful as methamphetamine antagonists, antipsychotic agents, cerebral medicaments, and analgesic agents. However, EP-0333071 and a subsequent presentation by Tsuchiya Y, et al, 200th American Chemical Society Meeting, Wash., DC, 1990 Abstract MEDI0015, do not suggest or disclose the compounds of the present invention which contain reduced [.PSI.CH.sub.2 NH] amide bond replacements in the 8,9 position of NT(8-13).
Lugrin D, et al, European Journal of Pharmacology 1991;205:191-98, disclosed a series of pseudopeptide analogs of neurotensin. They systematically replaced the five peptide bonds in neurotensin (8-13) with CH.sub.2 NH (.PSI., reduced) bonds. An analog containing the [.PSI.CH.sub.2 NH] in the 8,9 position of NT(8-13) (Lys[.PSI.CH.sub.2 NH]Lys-Pro-Tyr-Ile-Leu) (Seq ID No: 2) was found to be as potent as NT(8-13).
The compound first disclosed by Lugrin D, et al, in European Journal of Pharmacology 1991;205:191-8 was subsequently demonstrated to have analgesic activity when administered directly into the brain, e.g., intracerebral ventricular administration (ICV) (Dubuc I, et al, European Journal of Pharmacology 1992;219:327-9). However, there was no disclosure regarding peripheral administration of this compound. We have found that the compound is not active in a behavioral model, a test which is predictive of antipsychotic efficacy (see hereinafter table Biological Activity of Compounds of Formula I). When this compound was tested in two analgesic models, it was completely inactive in the rat tail pressure assay. This assay was carried out according to the modifications outlined in Winder CV, et al, Archs Int Pharmacodyn Ther 1959;122:301-11 of the method of Green AF, Br J Pharmacol 1951;6:572-87. This test is specific for agents which produce analgesia directly on the CNS. The compound did have weak activity in the acetic acid-induced writhing assay. However, this test, unlike the rat tail pressure assay, is sensitive not only to centrally acting analgesics but additionally anti-inflammatory agents which act in the periphery. We have surprisingly and unexpectedly found, in contrast to the reduced bond analog previously disclosed, the confounds of the present invention have potent activity in both the acetic acid-induced writhing test as well as the rat tail pressure assay indicating they are centrally acting analgesics. Thus, the compounds of the present invention demonstrate a significant advance over the compounds disclosed in EP-0333071 and Lugrin D, et al, European Journal of Pharmacology 1991;205:191-8. They represent the first example of 8,9[.PSI.CH.sub.2 NH] reduced bond isostere of NT(8-13) which have CNS activity as analgesics or antipsychotic agents when administered peripherally.
Further we have demonstrated that dialkyl amino substituted acetic acids, for example, bis(3-aminopropyl), bis(4-aminobutyl), and bis(3-guanidinylpropyl) substituted acetic acids can serve to replace the Arg-Arg residues in NT (8-13).